Lockout device for controlled release of drug from patient-activateddispenser

ABSTRACT

A method of controlling access to a drug in an aerosol drug delivery device by an electronic lock and key means is disclosed. Access is limited to the intended user by providing the intended user with a uniquely coded, machine readable key means that matches the unique code of the lock means. Contacting matching lock and key means signals a controlling means to allow use of the device. Specifically, the method is applied to a method of pain control provided by the intrapulmonary delivery of a pharmaceutically active pain relief formulation. The formulation is automatically released from a hand-held, self-contained, portable device comprised of a means for automatically releasing a measured amount of drug into the inspiratory flow path of a patient in response to information obtained from a means for measuring and separately determining inspiratory flow rate and inspiratory volume of a patient. Reproducible dosing is obtained by providing for automatic release in response to a separately measured inspiratory rate and inspiratory volume. To obtain repeatability in dosing the narcotic formulation is repeatedly released at the same measured (1) inspiratory flow rate and (2) inspiratory volume. To maximize the efficiency of the delivery the narcotic formulation is released at (1) a measured inspiratory flow rate in the range of from about 0.10 to about 2.0 liters/second and (2) a measured inspiratory volume in the range of about 0.15 to about 0.8 liters. Abuse of narcotic formulations is avoided by providing a tamper-resistant device which includes a variety of security features including an electronic lock and key means and a pre-programmed microprocessor designed to avoid overdosing.

CROSS-REFERENCE

This application is a continuation-in-part of earlier filed applicationSer. No. 08/011,289 filed Jan. 29, 1993, now abandoned which applicationis incorporated herein by reference and to which application is claimedpriority under 35 USC §120.

FIELD OF THE INVENTION

This invention relates generally to controlling access to drugscontained in a drug delivery device. More specifically, this inventionrelates to a microprocessor controlled locking system that allows accessto a narcotic drug only to an intended user possessing a uniquely codedmachine readable access device specifically read by a locking system ona drug delivery device for intrapulmonary drug delivery.

BACKGROUND OF THE INVENTION

Controlled access to a drug or medication is of paramount importance incases where the drug is a narcotic or is potentially toxic to anunintended user. A user for whom the drug is not intended, such as achild, may be harmed by such access. In the case of narcotics where theuse of the drug is greatly restricted, unintended use is not onlypotentially dangerous but illegal.

However, the on-demand administration of drug (e.g., a narcotic, ananalgesic, or a therapeutic, such as insulin) which allows the patientto control administration of his medication has proven to be aneffective method of maintaining effective blood levels of the drug; orallows a rapid concentration increase of the drug for rapidphysiological effect.

Narcotic therapy forms the mainstay of pain management. These drugs canbe administered in many forms to patients with postsurgical and otherforms of acute and chronic pain. Morphine, one of the oldest narcotics,is available for administration in tablet or in injectable form.Fentanyl, a synthetic narcotic, was first synthesized in 1960 by PaulJanssen and found to be 150 times more potent than morphine [TheodoreStanley, "The History and Development of the Fentanyl Series," Journalof Pain and Symptom Management (1992) 7:3 (suppl.), S3-S7]. Fentanyl andits relatives Sufentanil and Alfentanil are available for delivery byinjection. In addition, fentanyl is available for administration by atransdermal delivery system in the form of a skin patch [Duragesic™(fentanyl transdermal system) package insert, Janssen Pharmaceutica,Piscataway, N.J. 08855, Jan.-Jun. 1991].

A feature of the synthetic narcotic fentanyl is that is has a more rapidtime to onset and a shorter duration of action than morphine. This makesfentanyl a useful drug for the management of acute pain. Currently,fentanyl is typically given by intravenous injection for acute painmanagement. Although fentanyl can be given by a transdermal patch,transdermal delivery of fentanyl is designed for longterm administrationof the drug and does not lend itself to achieving a peak level rapidlyfor a short-term effect.

An alternative to delivery by injection for narcotics is delivery byinhalation. Morphine [J. Chrusbasik et al., "Absorption andBioavailability of Nebulized Morphine," Br. J. Anaesth. (1988) 61,228-30], fentanyl [M. H. Worsley et al., "Inhaled Fentanyl as a Methodof Analgesia," Anaesthesia (1990) 45, 449-51], and sufentanil [A. B.Jaffe et al., "Rats Self-administer Sufentanil in Aerosol Form,"Psychopharmacology, (1989) 99, 289-93] have been shown to be deliverableas aerosols into the lung. The pilot study described by Worsleysuggested that "inhaled fentanyl is an effective, safe and convenientmethod of analgesia which merits further investigation."

Inhalation of a potent synthetic narcotic aerosol provides a mechanismfor the non-invasive delivery of rapid-acting boluses of narcotic. Theon-demand administration of boluses of narcotic coupled with acontrolled baseline intravenous infusion of narcotic is termed"patient-controlled analgesia" (PCA) and has been found to be a veryeffective means of postoperative pain management.

On-demand analgesia was first introduced in 1968 by Schetzer who showedit to be an effective mechanism for treating postoperative patients[Maureen Smythe, "Patient-Controlled Analgesia: A Review,"Pharmacotherapy (1992), 12:2, 132-43]. Prior to the availability ofpatient-controlled analgesia, the paradigm for postoperative painmanagement consisted of intermittent intramuscular injections ofnarcotic. The cycle of the patient feeling pain, calling the nurse whothen must locate and bring the drug to the bedside for administrationresults in suboptimal postoperative pain management [Philip Shade,"Patient-controlled Analgesia: Can Client Education Improve Outcomes?,"Journal of Advanced Nursing (1992) 17, 408-13]. Postoperative painmanagement by intermittent narcotic administration has been shown to bea largely ineffective method of pain management for many of the patientsundergoing the more than 21 million surgical procedures in the UnitedStates each year [John Camp, "Patient-Controlled Analgesia," AFP (1991),2145-2150]. Even if every patient reliably received a constant dose ofnarcotic postoperatively, studies of therapeutic narcoticpharmacokinetic data have shown that patient variability makes such anapproach fundamentally unsound and potentially dangerous [L. E. Mather,"Pharmacokinetics and Patient-Controlled Analgesia," ActaAnaesthesiologica Belgica (1992) 43:1, 5-20].

The first commercial device for automatically providing intravenouspatient-controlled analgesia was developed in Wales in the mid-1970s.This device, the Cardiff Palliator (Graesby Medical Limited, UnitedKingdom) is the predecessor of numerous currently availablecomputer-controlled patient-controlled analgesia intravenous pumps[Elizabeth Ryder, "All about Patient-Controlled Analgesia," Journal ofIntravenous Nursing (1991) 14, 372-81]. Studies using these computercontrolled intravenous narcotic infusion pumps have shown that smalldoses of narcotics given on demand by the patient provided superior painrelief when compared with intermittent intramuscular administration ofthese drugs [Morton Rosenburg, "Patient-Controlled Analgesia," J. OralMaxillofac Surg (1992) 50, 386-89].

These computer-controlled pumps typically allowed for the programming offour different parameters: 1) basal intravenous narcotic infusion rate;2) the bolus of narcotic to be delivered on each patient demand; 3) themaximum hourly total dose of narcotic to be allowed; and 4) the lockoutperiod between doses. Typical programming for postoperative painmanagement with intravenous fentanyl might be a basal infusion rate of20 μg/hr, a bolus demand dose of 20 μg, a maximum hourly does of 180 μg,and a lockout period between doses of 5 minutes. In a study of 30patients treated for postoperative pain with intravenous fentanylpatient-controlled analgesia, the minimum effective concentration (MEC)of fentanyl in the blood required to achieve pain relief in the group ofpatients studies was found to range from 0.23 to 1.18 ng/ml. Clinicallysignificant respiratory depression was not seen in this study consistentwith published data indicating that a fentanyl concentration of 2 ng/mlin the blood is typically required to depress the respiratory rate[Geoffrey Gourlay et al., "Fentanyl Blood Concentration--AnalgesicResponse Relationship in the treatment of Postoperative Pain," AnesthAnalg (1988) 67, 329-37].

The administration of narcotic for pain management is potentiallydangerous because overdoses of narcotics will cause complications suchas respiratory depression. The patient's respiratory rate is decreasedby the administration of narcotics. This decrease in respiratory ratemay not be associated with a change in respiratory tidal volume [Miller,Anesthesia (2nd ed), Churchill Livingston, I, 762]. The fourprogrammable parameters available on computer-controlled intravenouspatient-controlled analgesia infusion pumps must be selected so as tominimize the likelihood of narcotic overdose. The preferred technique isto set the basal infusion rate at a relatively low rate and increasethis rate based on how many times the patient presses the bolus demandbutton to self-administer supplemental drug.

As long as the patient himself or herself is the only one to push thedemand button, respiratory depression is unlikely. However, there havebeen documented cases of the patient's family and friends pressing thenarcotic demand button, for instance while the patient is sleeping[Robert Rapp et al., "Patient-controlled Analgesia: A Review of theEffectiveness of Therapy and an Evaluation of Currently AvailableDevices," DICP, The Annals of Pharmacotherapy (1989) 23, 899-9040].

It is a problem with patient-controlled analgesia that it must currentlybe performed using an intravenous infusion pump. This requires that anindwelling catheter be placed in the patient's vein and that the patienttransport a relatively bulky system with himself at all times to receivea baseline infusion of intravenous narcotic and allow for intermittenton-demand self-bolusing of additional narcotic in order to match thepatient's changing need for drug. A portable PCA device incorporating awristwatch-like interface has been described [D. J. Rowbotham, "ADisposable Device for Patient-Controlled Analgesia with Fentanyl,"Anaesthesia (1989) 44, 922-24]. This system incorporated some of thefeatures of computer-controlled programmable PCA infusion pumps such asbasal infusion rate and the amount of each bolus. However, this system,which involved the use of an intravenous catheter as seen in largerinfusion pumps, incorporated no provision to record accurately theactual dose of Fentanyl administered to the patient over time.

Although fentanyl can be administered by transdermal patch, this methodhas been found to be suboptimal for postoperative main management [K. A.Lehmann et al., "Transdermal Fentanyl for the Treatment of Pain afterMajor Urological Operations, Eur. J. Clin Pharmacol (1991) 21:17-21].Lehmann found that the low dose of narcotic delivered by transdermalfentanyl was inadequate to provide pain relief to many of his patientsand that boosting the baseline infusion rate of the patch would put somepatients at risk for having significant respiratory depression. Inaddition, he points out that if such a complication were to appear inconjunction with the delivery of narcotic by transdermal patch, theinfusion could not be quickly stopped because the "cutaneous fentanyldepot" created by the transdermal patch would cause narcotic infusion tocontinue even after removal of the patch.

Delivery of fentanyl by aerosol used in conjunction with anon-invasively delivered long-acting preparation of narcotic such asslow-release oral morphine or a fentanyl transdermal patch provides ameans for non-invasive administration of a basal rate of narcotic andrapid-acting boluses of narcotic to an ambulatory patient.

It is a problem with the aerosol delivery of fentanyl previouslydescribed that inefficient, bulky nebulizers must be used for theadministration of the drug. In addition, these nebulizers work byadministering from an open reservoir of the drug in aqueous solutionallowing the vapor to be generally distributed and creating thepotential for overdosing due to the lack of reproducible aerosoldelivery. In addition, abuse through theft of the aqueous-phase fentanyland subsequent unauthorized repackaging of this controlled substance inan aqueous injectable form are possible.

Because most surgery today is being done on ambulatory patients andbecause these patients are often rapidly discharged from the hospitaland because patient-controlled analgesia has been identified as thepreferred method of postoperative pain management, it is desirable tohave a safe, effective, and access-controlled method for non-invasive,ambulatory patient-controlled analgesia.

SUMMARY OF THE INVENTION

The present invention relates to a package containing medicine, thepackage being constructed so that it is difficult to open the packagewithout contacting a sensor on the package to a mating receptacle (suchas a serialized semiconductor) possessed by the patient for whom themedicine is intended. The mating receptacle bears a machine readablecode indicating the identity of the patient that is matched to thepackage containing the medicine. Contacting the package sensor to theserialized semiconductor provides a keying feature to allow the patientaccess to the medicine.

A particular and preferred means for permitting the package to beactivated by the patient, a Touch Serial Number (TSN, manufactured byDallas Semiconductor) as termed herein, includes a semiconductor encodedwith a device family code, a unique 48 bit serial number (providing2.8×10¹⁴ possible combinations), and a cyclic redundancy check(hereinafter CRC) byte, all housed in a metallic container. The frontsurface of the container serves as one electrical contact, while theback and side surfaces of the container serve as the other electricalcontact providing a 2-wire serial interface that allows the matingreceptacle to be reset; a command word to be written into the TSN; anddata to be read from the TSN.

A TSN is preferably attached to a means (such as a bracelet or badge)that allows the patient to wear the TSN. The package containing themedicine will include a microcomputer programmed with the family code,serial number and CRC byte of the matching TSN and will include aTSN-compatible serial port for contact with the TSN.

Programming of the microcomputer is accomplished by setting themicrocomputer to "learn" mode with a command sent by computer via thepackage's serial port. The TSN is then contacted to the package's serialport, allowing the microcomputer within the package to read the TSN'sdata and store the data in the microcomputer's internal non-volatilememory.

In a preferred method of using the device, the user will haveapproximately three seconds after turning on the package to contact hisor her TSN to the serial port. The package will then send a reset signalfrom the TSN port. If no TSN is attached, no acknowledgement of thereset signal will occur; the package will display an error message andhalt activation of the drug delivery mechanism. If a TSN is attached tothe package, the reset signal will be acknowledged. The packagemicrocomputer will respond by first sending a "read" command byte to theTSN. The microcomputer then reads the next 64 bits from the TSN's ROM.After each byte is read, it is compared to the corresponding serialnumber byte pre-programmed into the drug delivery device. When acomparison fails, such as when an invalid TSN or no TSN is contacted tothe serial port, the microcomputer is preferably programmed to displayan error message and halt activation of the device. Preferably, thecomparison and activation or deactivation operation occurs inapproximately 15 ms or less. In a preferred embodiment, 8 bytes are readfrom the TSN and compared to the serial number pre-programmed into thedrug delivery device. If the codes match, the drug delivery device willallow operation, giving the user time to administer a dose of the drugbefore the microcomputer deactivates the power source to the device.Preferably, the TSN is removed from the device after the serial numberhas been read by the device's microcomputer.

Another preferred embodiment of the invention is to require contact,reading, and comparison steps of the microcomputer to be performedduring the mechanical drug delivery step. In this embodiment, the drugdelivery device (such as a syringe, aerosol inhalant, or like) can beturned on but the activation of the delivery mechanism will not occurunless the contact, reading, and comparison steps are successfullyperformed and the serial numbers of the TSN and the drug delivery devicematch.

It is also an object of the invention to disclose a method of paincontrol provided by the intrapulmonary delivery of a pharmaceuticallyactive pain relief formulation. After electronically unlocking the drugdelivery device formulation is automatically released from a hand-held,self-contained, portable device. The device is comprised of theabove-described locking components, a means for automatically releasinga separately measured amount of drug into the inspiratory flow path of apatient in response to information obtained from determining, in realtime, both the inspiratory flow rate and inspiratory volume of apatient. Reproducible dosing is obtained by providing for automaticrelease in response to a measured inspiratory rate and inspiratoryvolume. The method involves measuring for, calculating and/ordetermining a firing point or drug release decision based on theinstantaneously (or real time) calculated, measured and/or determinedinspiratory flow rate and inspiratory volume points. To obtainrepeatability in dosing the narcotic formulation is repeatedly releasedat the same measured (1) inspiratory flow rate and (2) inspiratoryvolume. To maximize the efficiency of the delivery the narcoticformulation is released at (1) a measured inspiratory flow rate in therange of from about 0.10 to about 2.0 liters/second and (2) a measuredinspiratory volume in the range of about 0.15 to about 0.8 liters. Thedevice may include other security features such as a pre-programmedmicroprocessor designed to avoid overdosing and may include the narcoticin a low boiling point solvent so that opening the container results inessentially immediate loss of the entire contents of the container asthe solvent vaporizes.

It is an object of this invention to describe a method of aerosolizeddelivery of potent narcotic in a safe and effective manner.

It is another object of the invention to describe a method ofrestricting access to a potent narcotic in a drug delivery device, suchas an aerosol delivery device and a lock and key mechanism (such as anelectronic key) that allows the intended user access to the drug andprevents access by unintended users. In a preferred embodiment the usertouches his uniquely coded, machine readable key (such as a TSN) to alock portion (such as a TSN interface) capable of reading the key anddiscerning a match or mismatch of the unique code of the key and thelocking portion. A code match results in the release of a lock onactivation of the drug delivery device allowing the user to receive adose of the drug.

Another object of the invention is to provide controlled access to anarcotic drug in an aerosol drug delivery device by providing anelectronic key for access control whereby the locking portion of theelectronic key is affixed to the aerosol container and the key portionof the electronic key is affixed to a substrate that is carried or wornby the user (e.g., a bracelet, a badge, a card, or the like).

An advantage of the invention is that the drug contained in thecontrolled access drug delivery device is accessible only to an intendeduser.

Another advantage of the invention in one embodiment the drug isdissolved in a solvent that vaporizes at normal atmospheric pressure.Bypassing the electronic key access mechanism to access the drugrequires breaking open the pressurized drug-containing canister. Whenthe canister is opened to atmospheric pressure, the entire contents isimmediately dispersed making the drug unavailable to the unintendeduser.

Another advantage of the invention is that a controlled-access drugdelivery device prevents access to unintended users and will thereforeoffer less liability risk to the manufacturer and the supplier of thedevice.

Another advantage of the invention is that the controlled access drugdelivery device prevents access to the drug by children making itpossible for the user to treat himself in his home.

Yet another advantage of the invention is that the electronic keyprovides a unique coding of each drug delivery device and its associatedkey such that one or more devices can be programmed with a unique codethat is also encoded on the key portion (such as a TSN) of theelectronic key device.

An advantage of the present invention is that it can be used forambulatory patients with a significantly reduced risk of narcotic abuse.

Another object is to provide a method of managing the pain of ambulatorypatients wherein aerosolized narcotic formulation is repeatedlydelivered to the patient at the same measured inspiratory volume (in therange of 0.15 to 0.8 liters and the same measured inspiratory flow rate(in the range of 0.1 to 2.0 liters per sec) after electronicallyunlocking the delivery device.

Another feature of this invention is that formulations of narcotics suchas fentanyl and a highly volatile propellant provide for a fundamentallytamper-resistant package making it difficult for the contained fentanylto be illicitly repackaged in an injectable form.

It is another object of the invention to provide a metered-dose inhalercanister comprising a formulation of narcotic such as fentanyl packagedin a manner such that it can only be used in conjunction with aparticular electronically locked apparatus described.

Another advantage is that the device can be programmed to provide aminimum required time interval between doses.

Another advantage of the invention is that the device can be programmedso as to control the maximum amount of narcotic delivered within aperiod of time.

Still another advantage is that dosing of narcotics can be controlled sothat aerosol delivery is possible and patients can obtain quick painrelief using such.

Yet another advantage is to provide a device which can be electronicallylocked and simultaneously programmed to control the maximum amount ofnarcotic drug delivered within a given period of time and provide for aminimum required time interval between the delivery of doses.

A feature of the invention is that it can monitor the amount ofaerosolized narcotic delivered to a patient (e.g. mg of formulation) andrecord amounts and times of delivery for review by a treating physician.

Another advantage of the invention is that the apparatus can monitorrespiratory rate to ensure that respiratory depression has notsupervened prior to further administration of narcotic.

Another object of this invention is to provide an apparatus which can beelectronically locked and can analyze the breathing pattern of thepatient not only to determine the respiratory rate prior to delivery butalso to determine the inspiratory flow profile characteristics so as todetermine the optimal point in the inspiratory cycle for delivery ofaerosolized potent narcotic.

Yet another object of this invention is to further provide aerosolizednaloxone which may be administered to counteract the effects ofadministered potent narcotic in the event of the development ofcomplications such as respiratory depression due to overdose of thenarcotic.

Another advantage is that the method described provides forelectronically coded access and reproducible delivery of narcotics suchas fentanyl wherein the reproducibility is a critical part of safetycausing each dose of narcotic to have the same clinical effect.

Another object is to provide an electronic lock-and-key system whichallows only the intended authorized patient to inhale aerosolizednarcotic from the described apparatus.

These and other objects, advantages and features of the presentinvention will become apparent to those skilled in the art upon readingthis disclosure in combination with drawings wherein like numerals referto like components throughout.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a drug delivery device;

FIG. 2 is a cross-sectional view of a more preferred embodiment of adrug delivery device;

FIG. 3 is a perspective view showing a pressurized canister with thecanister cover components disconnected;

FIG. 4 is a perspective view of another embodiment of the covercomponents connected and the canister held therein;

FIG. 5 is a graph showing data points plotted in four general areas withthe points plotted relative to inspiratory flow rate (on the abscissa)and inspiratory volume (on the ordinate) in two dimensions;

FIG. 6 is a graph showing the four general areas plotted per FIG. 1 nowplotted with a third dimension to show the percentage of drug reachingthe lungs based on a constant amount of drug released;

FIG. 7 is a three dimensional graph showing the therapeutic values forinspiratory flow rate and inspiratory volume which provide better drugdelivery efficiency;

FIG. 8 shows a preferred range of the valves shown in FIG. 7;

FIG. 9 shown a particularly preferred range for the valves of FIG. 7;

FIG. 10 is a schematic diagram of an aqueous system drug deliverydevice; and

FIG. 11 is a schematic diagram of an unauthorized user lockout flowchartshowing electronic decisions made by the device in allowing access tothe drug delivery device.

FIG. 12 is a schematic flow chart of the device showing the bar codereader;

FIG. 13 is a schematic flow chart of the device showing the infraredcode reader;

FIG. 14 is a schematic flow chart of the device showing the radiofrequencies signal reader.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before the present method of pain management with electronicallycontrolled access and devices and formulations used in connection withsuch are described, it is to be understood that this invention is notlimited to the particular methodology, devices and formulationsdescribed, as such methods, devices and formulations may, of course,vary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to limit the scope of the present invention which will belimited only by the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms "a," "an," and "the" include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to "aformulation" includes mixtures of different formulations, reference to"an electronic access device" includes a plurality of such devices, andreference to "the method of preventing access" includes reference toequivalent steps and methods known to those skilled in the art, and soforth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the invention, the preferred methods andmaterials are now described. All publications mentioned herein areincorporated herein by reference to describe and disclose specificinformation for which the reference was cited in connection with.

The term "electronic key" refers to a means for providing a uniqueidentifying code to a component which prevents access to a device. Ingeneral, an electronic key locking unit on the drug delivery device isactivated or unlocked by an electronic key possessed by the intendeduser. Use of the drug delivery device is prevented without the use ofthe electronic key.

The term "intended user" refers to a user to whom the drug contained inthe drug delivery device of the invention is prescribed such by aprescribing physician. The intended user is the only person who isintended to possess the correct electronic key which may be a programmedTSN that matches the code of the TSN interface on the user's drugdelivery device.

The term "unintended user" refers to individuals who do not possess aTSN which matches the code of the TSN interface on the user's drugdelivery device.

The term "velocity of the drug" shall mean the average speed ofparticles moving from a drug release point such as a valve to apatient's mouth.

The term "dosing event" shall be interpreted to mean the administrationof analgesic drug to a patient in need thereof by the intrapulmonaryroute of administration which event may encompass electronicallyunlocking a device followed by one or more releases of analgesic drugformulation from an analgesic drug dispensing device over a period oftime of 15 minutes or less, preferably 10 minutes or less, and morepreferably 5 minutes or less, during which period multiple inhalationsare made by the patient and multiple doses of analgesic drug arereleased and inhaled. A dosing event shall involve the administration ofanalgesic drug to the patient in an amount of about 1 μg to about 100 mgin a single dosing event which may involve the release of from about 10μg to about 1000 mg of analgesic drug from the device.

The term "measuring" describes an event whereby both the inspiratoryflow rate and inspiratory volume of the patient is measured, calculatedand/or determined in order to determine an optimal point in theinspiratory cycle at which to release aerosolized narcotic formulation.It is also preferable to continue measuring inspiratory flow during andafter any drug delivery and to record inspiratory flow rate and volumebefore, during and after the release of drug. Such reading makes itpossible to determine if narcotic formulation was properly delivered tothe patient. A microprocessor or other device can calculate volume basedon a measured flow rate. When either flow rate or volume becomes knownin any manner it can be said to have been determined.

The term "monitoring" event shall mean measuring lung functions such asinspiratory flow, inspiratory flow rate, and/or inspiratory volume sothat a patient's lung function as defined herein, can be evaluatedbefore and/or after drug delivery thereby making it possible to evaluatethe effect of narcotic delivery on the patient's lung function.

The term "inspiratory flow rate" shall mean a value of air flowmeasured, calculated and/or determined based on the speed of the airpassing a given point in a measuring device assuming atmosphericpressure ±5% and a temperature in the range of about 10° C. to 40° C.

The term "inspiratory flow" shall be interpreted to mean a value of airflow calculated based on the speed of the air passing a given pointalong with the volume of the air that has passed that point with thevolume calculation being based on integration of the flow rate data andassuming atmospheric pressure ±5% and temperature in the range of about10° C. to about 40° C.

The term "inspiratory volume" shall mean a measured, calculated and/ordetermined volume of air passing a given point into the lungs of apatient assuming atmospheric pressure ±5% and a temperature in the rangeof 10° C. to 40° C.

The term "inspiratory flow profile" shall be interpreted to mean datacalculated in one or more events measuring inspiratory flow andcumulative volume, which profile can be used to determine a point withina patient's inspiratory cycle which is optimal for the release of drugto be delivered to a patient. The point within the inspiratory cyclewhere drug is released may be based on a point within the inspiratorycycle likely to result in the maximum delivery of drug and based and/oron a point in the cycle most likely to result in the delivery of areproducible amount of drug to the patient at each release of drug.Repeatability of the amount delivered is the primary criterion andmaximizing the amount delivered is an important but secondary criterion.Thus, a large number of different drug release points might be selectedand provide for repeatability in dosing provided the selected point isagain selected for subsequent releases. To insure maximum drug deliverythe point is selected within given parameters.

The term "analgesic drug" shall be interpreted to mean a drug fortreating symptoms of pain. Analgesic drugs may include one of:narcotics, nonsteroidal anti-inflammatory drugs and mixedagonist-antagonistic drugs such as butorphanol. Examples of usefulnarcotics drugs are described and disclosed within the Physicians DeskReference and the Drug Evaluations Annual 1993, published by theAmerican Medical Association, both of which are incorporated herein byreference. The invention encompasses the free acids, free bases, salts,hydrates in various formulations of analgesic drugs useful for paincontrol.

The term "therapeutic index" refers to the therapeutic index of a drugdefined as LD₅₀ /ED₅₀. The LD₅₀ (lethal dose, 50%) is defined as thedose of a drug which kills 50% of the tested animals, and the ED₅₀ isdefined as the effective dose of the drug for 50% of the individualstreated. Drugs with a therapeutic index near unity (i.e. LD₅₀ /ED₅₀ isapproximately equal to 1) achieve their therapeutic effect at doses veryclose to the toxic level and as such have a narrow therapeutic window,i.e. a narrow dose range over which they may be administered.

The terms "formulation" and "liquid formulation" and the like are usedinterchangeably herein to describe any pharmaceutically active drug byitself or with a pharmaceutically acceptable carrier in flowable formwhich is preferably a liquid. Such formulations are preferablysolutions, e.g. aqueous solutions, ethanolic solutions,aqueous/ethanolic solutions, saline solutions and colloidal suspensions.Formulations can be solutions or suspensions of drug in a low boilingpoint propellant.

The terms "lung function" and "pulmonary function" are usedinterchangeably and shall be interpreted to mean physically measurableoperations of a lung including but not limited to (1) inspiratory and(2) expiratory flow rates as well as (3) lung volume. Methods ofquantitatively determining pulmonary function are used to measure lungfunction. Quantitative determination of pulmonary function may beimportant when delivering analgesic drugs in that respiration can behindered or stopped by the overdose of such drugs. Methods of measuringpulmonary function most commonly employed in clinical practice involvetimed measurement of inspiratory and expiratory maneuvers to measurespecific parameters. For example, forced vital capacity (FVC) measuresthe total volume in liters exhaled by a patient forcefully from a deepinitial inspiration. This parameter, when evaluated in conjunction withthe forced expired volume in one second (FEV₁), allowsbronchoconstriction to be quantitatively evaluated. A problem withforced vital capacity determination is that the forced vital capacitymaneuver (i.e. forced exhalation from maximum inspiration to maximumexpiration) is largely technique dependent. In other words, a givenpatient may produce different FVC values during a sequence ofconsecutive FVC maneuvers. The FEF 25-75 or forced expiratory flowdetermined over the mid-portion of a forced exhalation maneuver tends tobe less technique dependent than the FVC. Similarly, the FEV₁ tends tobe less technique dependent than FVC. In addition to measuring volumesof exhaled air as indices of pulmonary function, the flow in liters perminute measured over differing portions of the expiratory cycle can beuseful in determining the status of a patient's pulmonary function. Inparticular, the peak expiratory flow, taken as the highest air flow ratein liters per minute during a forced maximal exhalation, is wellcorrelated with overall pulmonary function in a patient with asthma andother respiratory diseases. The present invention carries out treatmentby administering drug in a drug delivery event and monitoring lungfunction in a monitoring event. A series of such events may be carriedout and repeated over time to determine if lung function is improved.

Each of the parameters discussed above is measured during quantitativespirometry. A patient's individual performance can be compared againsthis personal best data, individual indices can be compared with eachother for an individual patient (e.g. FEV₁ divided by FVC, producing adimensionless index useful in assessing the severity of acute asthmasymptoms), or each of these indices can be compared against an expectedvalue. Expected values for indices derived from quantitative spirometryare calculated as a function of the patient's sex, height, weight andage. For instance, standards exist for the calculation of expectedindices and these are frequently reported along with the actualparameters derived for an individual patient during a monitoring eventsuch as a quantitative spirometry test.

In addition to the respiratory parameters measured by the device, thedevice is further equipped to be activated (unlocked) and deactivated(locked) by an electronic key device (such as the Touch Serial Numberdevice supplied by Dallas Semiconductor). The device is electronicallyconnected by means well known to those of skill in the art ofelectronics to the activation and/or actuation of the drug deliverydevice so as to control access to delivery of a drug contained in thedevice.

The term "CRC" is an abbreviation for cyclic redundancy check. A cyclicredundancy check or CRC is used in the TSN device and provides atechnique which generates a byte-wide value based on the devices familycode and serial number data--this number could then be used to verifythe integrity of the data downloaded from the drug delivery device fromthe TSN device. To perform the integrity check, the drug delivery devicewould apply the CRC generation algorithm to data received from the TSN.After all the data has been transferred, the drug delivery device wouldcompare the CRC value it calculated from the data stream against the CRCbyte transmitted by the TSN. If the values match, the drug deliverydevice would assume no errors occurred during the data transmission.Otherwise, the drug delivery device would request that the TSN data beretransmitted. Unless the correct data is transmitted to themicroprocessor of the drug delivery device the drug device cannot beactivated and drug cannot be released from the device.

General Methodology

The device and methodology make it possible to electronically controlaccess to a drug (such as a toxic or narcotic drug) prescribed to aspecific patient such that only the patient has access to the drug inthe intended dosages. The preferred means of controlling access is anelectronic key device with a uniquely coded key means (such as a TSN)and a lock means (such as a TSN interface) capable of reading the uniquecode and matching the code to a unique code in the internal memory ofthe lock means. If the codes match, the drug delivery device receives anacknowledgement signal, the drug delivery device is activated and theuser is able to access the drug. If the codes do not match, or if no keymeans is available, the drug delivery device receives no acknowledgementsignal and the drug delivery device is not activated and will notdispense drug.

A non-invasive means of pain management is provided in a manner whichmakes it possible to restrict access and maintain tight control over theamount of drug administered to a patient suffering with pain and toquickly and efficiently provide for pain relief. An essential feature ofthe invention is controlled access of intrapulmonary delivery ofanalgesic drug to the patient combined with drug delivery in acontrolled and repeatable manner. The device of the invention provides anumber of features which make it possible to control access and achievethe controlled and repeatable dosing procedure required for painmanagement. Specifically, the device is electronically locked and drugis not directly released by the patient in the sense that no button ispushed nor valve released by the patient applying physical pressure. Onthe contrary, the device of the invention provides that the valvereleasing analgesic drug is unlocked with an electronic key after whichthe valve is opened automatically upon receipt of a signal from amicroprocessor programmed to send a signal when data is received from amonitoring device such as an airflow rate monitoring device. A patientusing the device withdraws air from a mouthpiece and the inspiratoryrate, and calculated inspiratory volume of the patient is measured oneor more times in a monitoring event which determines an optimal point inan inhalation cycle for the release of a dose of analgesic drug.Inspiratory flow is measured and recorded in one or more monitoringevents for a given patient in order to develop an inspiratory flowprofile for the patient. The recorded information is analyzed by themicroprocessor in order to deduce a preferred point within the patient'sinspiratory cycle for the release of analgesic drug with the preferredpoint being calculated based on the most likely point to result in areproducible delivery event.

It is pointed out that the device of the present invention can be usedto, and actually does, improve the efficiency of drug delivery. However,this is not the critical feature. The critical feature is controlledaccess along with reproducibility of the release of a tightly controlledamount of drug at a particular point in the respiratory cycle so as toassure the delivery of a controlled and repeatable amount of drug to thelungs of each individual patient.

The combination of controlled access and automatic control of the valverelease, combined with frequent monitoring events in order to calculatethe optimal flow rate and time for the release of analgesic drug,combine to provide a repeatable means of delivering analgesic drug to apatient. Because the valve is released automatically and not manually,it can be predictably and repeatedly opened for the same amount of timeeach time or for the preprogrammed measured amount of time which isdesired at that particular dosing event. Because dosing events arepreferably preceded by monitoring events, the amount of analgesic drugreleased and/or the point in the inspiratory cycle of the release can bereadjusted based on the particular condition of the patient. Forexample, if the patient is suffering from a condition which allows for acertain degree of pulmonary insufficiency, such will be taken intoaccount in the monitoring event by the microprocessor which willreadjust the amount and/or point of release of the analgesic drug in amanner calculated to provide for the administration of the same amountof analgesic drug to the patient at each dosing event.

FIG. 5 is a two-dimensional graph wherein the inspiratory flow rate isplotted against the inspiratory volume. The patient's inspiratory flowrate and inspiratory volume may be simultaneously and separatelymeasured, calculated and/or determined. The measurement is taken and theinformation obtained from the measurement provided to a microprocessorwhich microprocessor is programmed to release drug (1) at the same pointrelative to inspiratory flow and inspiratory volume at each release ofdrug and (2) to select that point within prescribed parameters ofinspiratory flow rates and inspiratory volumes. In the particularresults plotted in FIG. 5 the microprocessor was programmed to releasedrug in four general areas with respect to the inspiratory flow rate andinspiratory volume parameters. This resulted in data points beingplotted in four general areas on the two-dimensional graph of FIG. 5.The four areas are labeled 1, 2, 3 and 4. In area 1 (showing solidtriangles), the drug was released when the patient's inspiratory flowrate was "slow to medium" (0.10 to 2.0 liters per sec) with an "early"inspiratory volume of 0.15 to 0.8 liters. In area 2 (showing opentriangles), the drug was released at a "slow" inspiratory rate/0.10 to1.0 liters/sec) and a "late" volume (1.6 to 2.8 liters). In area 3(showing solid diamonds), the drug was released at a "fast" inspiratoryflow rate (3.5 to 4.5 liters/sec) and a "late" volume. In area 4(showing solid circles), the drug was released at a "fast inspiratoryflow rate and an "early" inspiratory volume.

The results shown in FIG. 5 were obtained while administering aradioactively labeled drug to a human. After the administration of thedrug it was possible to determine not only the amount of drug, but thepattern of drug deposited within the lungs of the patient. Using thisinformation two conclusions were reached. Firstly, it was determinedthat it is important to simultaneously and separately determined (inreal time) both inspiratory flow rate and inspiratory volume whenproviding for intrapulmonary drug delivery. Changes in either parametercan greatly effect the amount of drug deposited. Thus, when treating apatient the drug should be released at approximately (±10%, preferably±5% and most preferable as close as possible to the first release point)the same inspiratory flow rate and inspiratory volume each time--goingback to the same point each time for the same patient ensures repeatabledosing. In practice the tighter the point is defined the greater therepeatability of dosing. However, if the point is defined to preciselyit can be difficult for the patient to obtain that rate/volume pointagain. Thus, some degree of tolerance is generally applied. Secondly, itwas found that within particular ranges with respect to inspiratory flowrate and inspiratory volume it was possible to obtain a consistentlyhigh percentage amount of drug deposited in the lung. Such results areshown graphically within the three dimensional graph as shown in FIG. 6.

The third dimension as shown in FIG. 6 (the height of the four columns)indicates the percentage amount of drug deposited based on the totalamount of drug released to the patient. The area labeled 1 clearlyshowed the highest percentage of drug delivered to the patient based onthe amount of drug released. Using this information it was possible tocalculate a specific area regarding inspiratory flow rate andinspiratory volume at which it is possible to obtain not only a highdegree of repeatability in dosing, but obtain a higher percentage ofdrug being delivered based on the percentage of drug released.Specifically, it was determined that the drug should be released withinan inspiratory flow rate range of 0.10 to 2.0 liters per second and atan inspiratory volume in the range of about 0.15 to about 0.80 liters.This range is shown by the rectangularly shaped column of FIG. 7.

In that intrapulmonary drug delivery systems often provide for erraticdosing it is important to provide a method which allows for consistent,repeatable dosing. This is obtained by simultaneously and separatelymeasuring both inspiratory flow rate and inspiratory volume a definingpoint by its abscissa and ordinate. If both measurements are separatelytaken the drug can be released anywhere along the abscissa and ordinatescales shown in FIG. 5. Once a point is selected (such as by randomlyselecting a point in box 1 of the graph of FIG. 5) that selected point(with the same coordinants) is used again and again by a given patientto obtain repeatable dosing. If only one parameter is measured (abscissaor ordinate) and drug is released based on that parameter the drugrelease point is defined by a line on the graph of FIG. 5. When drug isreleased again the release can be at any point on that line. Forexample, the inspiratory flow rate (measured horizontally on theabscissa) might be defined by a point. However, the inspiratory volume(which was not measured) would be defined only by a vertical line. Thus,subsequent releases would be at different volumes along that verticalline and the dosing would not be consistent. By measuring bothinspiratory flow rate on the abscissa and inspiratory volume on theordinant the coordinants will mark a point for drug release. That pointcan be found again and again to obtain repeatability in dosing. The samepoint should be selected each time as closely as possible and within amargin of errors of ±10% with respect to each criteria. The margin forerror can be increased and still maintain acceptable levels ofrepeatable dosing--but the error should keep the drug release pointinside the box 1 of FIG. 5.

By examining delivery of drug associated with the data points plotted inFIG. 5, it is possible to determine a preferred and particularlypreferred and most preferred range as per FIGS. 7, 8 and 9. Thepreferred range of FIG. 7 shows drug released at a volume of 0.15 to 0.8liters and rate of 0.10 to 2.0 liters/second. The particularly preferredrange plotted in FIG. 8 indicates that the inspiratory flow should bewithin the range of 0.2 to about 1.8 liters per second with aninspiratory volume in the range of 0.15 to about 0.4 liters. The mostpreferred range (FIG. 9) is from about 0.15 to about 1.8 liters persecond for the inspiratory flow rate and about 0.15 to about 0.25 litersfor the inspiratory volume. Thus, the essence of the invention is (1)repeatedly delivering aerosolized analgesic formulation to a patient atthe same simultaneously and separately measured inspiratory flow rateand inspiratory volume and (2) releasing drug to the patient withinspecified therapeutically effective ranges as shown within FIGS. 7, 8and 9. The invention involves releasing drug (after measuring) insidethe ranges as per FIGS. 7, 8 or 9. Thus, the release could begin insideor outside the range. Preferable the drug release begins inside therange and more preferable begins and ends inside the ranges of FIGS. 7,8 or 9.

The methodology of the invention may be carried out using a portable,hand-held, battery-powered device. As per U.S. patent application Ser.No. 08/002,507 filed Jan. 29, 1993 incorporated herein by reference. Inaccordance with another system the methodology of the invention could becarried out using the device, dosage units and system disclosed in U.S.patent application Ser. No. 08/247,012 filed May 20, 1994. In accordancewith the system the analgesic drug (which is preferably a narcotic) isincluded in an aqueous formulation which is aerosolized by moving theformulation through a porous membrane. Alternatively, the methodology ofthe invention could be carried out using a mechanical (non-electronic)device. Those skilled in the art recognized that various components canbe mechanically set to actuate at a given inspiratory flow rate (e.g. aspring biased valve) and at a given volume (e.g. a spinable flywheelwhich rotates a given amount per a given volume). The components of suchdevices could be set to allow drug release inside the parameters ofFIGS. 3, 4 or 5.

The drug which is released to the patient may be in a variety ofdifferent forms. For example, the drug may be an aqueous solution ofdrug, i.e., drug dissolved in water and formed into small particles tocreate an aerosol which is delivered to the patient. Alternatively, thedrug may be in a solution wherein a low-boiling point propellant is usedas a solvent. In yet, another embodiment the drug may be in the form ofa dry powder which is intermixed with an airflow in order to provide forparticleized delivery of drug to the patient. Regardless of the type ofdrug or the form of the drug formulation, it is preferable to createdrug particles having a size in the range of about 0.5 to 5 microns. Bycreating drug particles which have a relatively narrow range of size, itis possible to further increase the efficiency of the drug deliverysystem and improve the repeatability of the dosing. Thus, it ispreferable that the particles not only have a size in the range of 0.5to 5 microns but that the mean particle size be within a narrow range sothat 80% or more of the particles being delivered to a patient have aparticle diameter which is within ±50% of the average particle size,preferably ±20% and more preferably ±5% of the average particle size.

The velocity at which the aerosolized drug is released to the patient isalso important in terms of obtaining a high degree of repeatability indosing and providing for a high percentage of drug being delivered tothe patient's lungs. Most preferably, the drug is released from acontainer in a direction which is normal to the patient's airflow.Accordingly, the drug may be released directly upward so that its flowis at a 90° angle with respect to the patient's inspiratory flow whichis directly horizontal. After being released, the drug velocitydecreases and the drug particles remain suspended for a sufficientperiod of time to allow the patient's inspiration to draw the drug intothe patient's lungs. The velocity of drug released in the direction fromthe drug release point to the patient may match the patient'sinspiratory flow rate but is preferably slower that the patient'sinspiratory flow rate and is most preferably about zero. The velocitymay be slightly negative, i.e., in a direction away from the patient.The velocity may range from -2.0 liters/sec to 2.0 liters/sec and ispreferably zero. It is not desirable to project the drug toward thepatient at a rate above the speed of the patient's breath as such mayresult in drug being deposited on the back of the patient's throat.Thus, the drug release speed should be equal to or less than the breathspeed. The actual speed of release can vary depending on factors such asthe particle size, the particle composition and the distance between thepoint of release and the patient. The velocity is preferably such thatthe particles will (due to air resistance) slow to zero velocity aftertraveling a distance of about 2 centimeters or less. In general, theshorter the distance required to slow the particles to zero velocity thebetter.

An aerosol may be created by forcing drug through pores of a membranewhich pores have a size in the range of about 0.25 to 2.5 microns. Whenthe pores have this size the particles which escape through the pores tocreate the aerosol will have a diameter in the range of 0.5 to 5microns. Drug particles may be released with an air flow intended tokeep the particles within this size range. The creation of smallparticles may be facilitated by the use of the vibration device whichprovides a vibration frequency in the range of about 800 to about 4000kilohertz. Those skilled in the art will recognize that some adjustmentscan be made in the parameters such as the size of the pores from whichdrug is released, vibration frequency, pressure, and other parametersbased on the density and viscosity of the formulation keeping in mindthat the object is to provide aerosolized particles having a diameter inthe range of about 0.5 to 5 microns.

The drug formulation may be a low viscosity liquid formulation which ispreferably a formulation which can be aerosolized easily and includesrespiratory drug formulations currently used in nebulizers. Theviscosity of the drug by itself or in combination with a carrier must besufficiently low so that the formulation can be forced out of openingsto form an aerosol, e.g., using 20 to 200 psi to form an aerosolpreferably having a particle size in the range of about 0.5 to 5microns.

Drug may be stored in and/or released from a container of any desiredsize. In most cases the size of the container is not directly related tothe amount of drug being delivered in that most formulations includerelatively large amounts of excipient material e.g. water or a salinesolution. Accordingly, a given size container could include a wide rangeof different doses by varying drug concentration.

The amount of analgesic drug delivered to the patient will vary greatlydepending on the particular drug being delivered. In accordance with thepresent invention it is possible to deliver a wide range of analgesicdrugs. For example, drugs included within the container could be drugswhich have a systemic effect such as narcotic drugs, for examplemorphine, fentanyl and sufentanil. Other useful drugs include those in aclass known as NSAID's or non-steroidal anti-inflammatorydrugs'particularly ketorolac and including acetaminophen and ibuprofen.

Drug containers may include indices which may be electronic and may beconnected to a power source such as a battery. When the indices are inthe form of visually perceivable numbers, letters or any type of symbolcapable of conveying information to the patient. Alternatively, theindices may be connected to a power source such as a battery when theindices are in the form of magnetically, optically or electronicallyrecorded information which can be read by a drug dispensing device whichin turn provides visual or audio information to the user. The indicescan be designed for any desired purpose but in general provides specificinformation relating to the day and/or time which the drug within acontainer should be administered to the patient. Such indices mayrecord, store and transfer information to a drug dispensing deviceregarding the number of doses remaining in the container. The containersmay include labeling which can be in any format and could include daysof the month or other symbols or numbers in any variation or language.

In addition to disclosing specific information regarding the day andtime for drug delivery the indices could provide more detailedinformation such as the amount of drug dispensed from each containerwhich might be particularly useful if the containers included differentamounts of drug. Further, magnetic, optical and/or electronic indicescould have new information recorded onto them which information could beplaced there by the drug dispensing device. For example, a magneticrecording means could receive information from the drug dispensingdevice indicating the precise time which the drug was actuallyadministered to the patient. In addition to recording the time ofdelivery the device could monitor the expected efficacy of the deliverybased on factors such as the inspiratory flow rate which occurredfollowing the initial release of drug. The information recorded couldthen be read by a separate device, interpreted by the care-giver andused to determine the usefulness of the present treatment methodology.For example, if the patient did not appear to be responding well but therecorded information indicating that the patient had taken the drug atthe wrong time or that the patient had misdelivered drug by changinginspiratory flow rate after initial release it might be determined thatfurther education in patient use of the device was needed but that thepresent dosing methodology might well be useful. However, if therecordings indicated that the patient had delivered the drug using theproper techniques and still not obtained the correct results a differentdrug or dosing methodology might be recommended.

The method of managing a patient's pain may be carried out using ahand-held, portable device comprised of (a) a device for holding adisposable package comprised of at least one but preferably a number ofdrug containers, (b) a propellant or a mechanical mechanism for movingthe contents of a container through a porous membrane to create anaerosol, and (c) an electronic access control device which preventsrelease of drug unless activated by an electronic key. The device alsopreferably includes (d) a monitor for analyzing the inspiratory flow,rate and volume of a patient, and (e) a switch for automaticallyreleasing or firing the mechanical means after the inspiratory flowand/or volume reaches a threshold level. The device may also include atransport mechanism to move the package from one container to the next.The entire device is self-contained, light weight (less than 1 kgpreferably less than 0.5 kg loaded) and portable.

The device may include a mouth piece at the end of the flow path, andthe patient inhales from the mouth piece which causes an inspiratoryflow to be measured within the flow path which path may be in anon-linear flow-pressure relationship. This inspiratory flow causes anair flow transducer to generate a signal. This signal is conveyed to amicroprocessor which is able to convert, continuously, the signal fromthe transducer in the inspiratory flow path to a flow rate in liters perminute. The microprocessor can further integrate this continuous airflow rate signal into a representation of cumulative inspiratory volume.At an appropriate point in the inspiratory cycle, the microprocessor cansend a signal to an actuation means (and/or a vibration device below theresonance cavity). When the actuation means is signaled, it causes themechanical means (by pressure or vibration) to move drug from acontainer on the package into the inspiratory flow path of the deviceand ultimately into the patient's lungs. After being released, the drugand carrier will pass through a porous membrane which is vibrated toaerosolize the formulation and thereafter the lungs of the patient.Containers and systems of the type described above are disclosed anddescribed in U.S. patent application Ser. No. 08/247,012 filed May 20,1994 which is incorporated herein by reference to disclose and describesuch containers and systems.

It is important to note that the firing threshold of the device is notbased on a single criterion such as the rate of air flow through thedevice or a specific time after the patient begins inhalation. Thefiring threshold is based on an analysis of the patient's inspiratoryflow profile. This means that the microprocessor controlling the devicetakes into consideration the instantaneous air flow rate as well as thecumulative inspiratory flow volume. Both are simultaneously consideredtogether in order to determine the optimal point in the patient'sinspiratory cycle most preferable in terms of (1) reproduciblydelivering the same amount of drug to the patient with each release ofdrug by releasing drug at the same point each time and maximizing theamount of drug delivered as a percentage of the total amount of drugreleased by releasing with the parameters described herein.

The device preferably includes a means for recording a characterizationof the inspiratory flow profile for the patient which is possible byincluding a microprocessor in combination with a read/write memory meansand a flow measurement transducer. By using such devices, it is possibleto change the firing threshold at any time in response to an analysis ofthe patient's inspiratory flow profile, and it is also possible torecord drug dosing events over time. In a particularly preferredembodiment the characterization of the inspiratory flow can be recordedonto a recording means on the disposable package.

The details of a drug delivery device which includes a microprocessorand pressure transducer of the type used in connection with the presentinvention are described and disclosed within U.S. patent applicationSer. No. 07/664,758 filed on Mar. 5, 1991 entitled "Delivery of AerosolMedications for Inspiration" which application is incorporated in itsentirety herein by reference, and it is specifically incorporated inorder to describe and disclose the microprocessor and program technologyused therewith. (See also PCT application 92-01815 also incorporated byreference.)

The use of such a microprocessor with a drug delivery device isdisclosed in our earlier filed U.S. patent application Ser. No.08/065,660 filed May 21, 1993 incorporated herein by reference. Thepre-programmed information is contained within a nonvolatile memorywhich can be modified via an external device. In another embodiment,this pre-programmed information is contained within a "read only" memorywhich can be unplugged from the device and replaced with another memoryunit containing different programming information. In yet anotherembodiment, a microprocessor, containing read only memory which in turncontains the pre-programmed information, is plugged into the device. Foreach of these three embodiments, changing the programming of the memorydevice readable by a microprocessor will radically change the behaviorof the device by causing the microprocessor to be programmed in adifferent manner. This is done to accommodate different drugs fordifferent types of treatment.

In a preferred embodiment of the methodology of the invention severaldifferent criteria are considered. (1) The inspiratory flow rate andinspiratory volume are simultaneously and separately measured to insurerepeatability. (2) The drug is released inside the parameters of FIGS.7, 8 or 9 with FIG. 9 parameters being most preferred. (3) The particlesize of the released drug is in the range of 0.5 to 5 microns and 80% ormore and the particles have the same size as the average particle size±10% in size. (4) The drug particles are released at a velocity which isobtained at a flow rate in the range of greater than -2.0 liters/sec.and less than 2.0 liters/sec. As indicated early the actual velocity canvary based on a number of factors. The release velocity should bedetermined so that the particles are at or are slowed to zero velocityafter traveling about 0.5 to 2 cm from the release point. The speedbeing measured from the drug release point in a direction toward theback of the throat of the patient.

After dosing a patient with a systemic analgesic drug it is desirable totake blood samples and make adjustments as needed to obtain the desireddrug to blood ratio. In accordance with all methods the patient does notpush a button to release drug. The drug is released automatically bysignals from the microprocessor using measurements obtained.

In another embodiment of the invention whereby the blood level of thedrug is monitored and recorded in a machine readable format, the drugdelivery device (such as an aerosol delivery device) can be programmedto restrict access to the drug by a user whose blood level of the drug(or rate of respiration) is in an unacceptable range. For example, aprobe that monitors blood drug level in a machine readable format (orrespiration rate monitor) can be coupled to a microprocessorelectronically connected to the activation mechanism of the drugdelivery device. Upon reading the data from the probe the electroniclock means may be signalled to provide access or not depending onwhether the probe reading falls within a preprogrammed acceptable rangeof values.

The amount of analgesic drug delivered to the patient will vary greatlydepending on the particular drug being delivered. In accordance with thepresent invention it is possible to deliver a wide range of differentanalgesic and narcotic drugs with a preferred drug being sufentanilwhich is generally administered to a patient in an amount in the rangeof about 2.5 μg-100 μg. It is pointed out that sufentanil isapproximately ten times more potent than fentanyl (another preferreddrug) so that fentanyl is generally delivered to a patient in an amountof about 25 μg-1000 μg. These doses are based on the assumption thatwhen interpulmonary delivery methodology is used the efficiency of thedelivery is approximately 10% and adjustments in the amount releasedmust be made in order to take into account the efficiency of the device.The differential between the amount of analgesic drug actually releasedfrom the device and the amount of analgesic drug actually delivered tothe patient varies due to a number of factors. In general, devices usedwith the present invention can have an efficiency as low as 10% and ashigh as 50% meaning that as little as 10% of the released analgesic drugmay actually reach the circulatory system of the patient and as much as50% might be delivered. The efficiency of the delivery will varysomewhat from patient to patient and must be taken into account whenprogramming the device for the release of analgesic drug. In general, aconventional metered dose inhaling device is about 10% efficient.

When administering analgesic drug, the entire dosing event can involvethe administration of anywhere from 1 μg to 100 mg, but more preferablyinvolves the administration of approximately 10 μg to 10 mg. The largevariation in the amounts which might be delivered are due to the factthat different drugs have greatly different potencies and may bedelivered from devices which vary greatly in terms of the efficiency ofdrug delivered. The entire dosing event may involve several inhalationsby the patient with each of the inhalations being provided with multiplebursts of analgesic drug from the device.

In addition to drug potency and delivery efficiency, analgesic drugsensitivity must be taken into consideration. The present inventionmakes it possible to vary dosing over time if analgesic sensitivitychanges and/or if user compliance and/or lung efficiency changes overtime.

Dynamic Particle Size Adjustment

The size of aerosolized particles released from a drug delivery devicecan change based on the surrounding atmosphere. For example, theparticles can decrease in size due to evaporation of water from theparticles or can increase in size due to the presence of a highconcentration of water vapor within the air, i.e., high humidity. Inorder to compensate for differences in the surrounding atmosphere andprovide for consistent particle size it may be desirable to include ameans for adding energy to the surrounding atmosphere so as to minimize,to the extent possible, the effect of water vapor in the surroundingatmosphere. Alternatively, it may desirable to saturate the surroundingatmosphere with water vapor. Either method could provide for consistencyin the size of particles delivered to the patient. Means for carryingout the dynamic particle size adjustment are disclosed within U.S.patent application Ser. No. 08/313,461 filed Sep. 27, 1994, entitled"Dynamic Particle Size Control for Aerosolized Drug Delivery" whichapplication is incorporated herein by reference in its entirety andincoroprated specifically to disclose means for adjusting aerosolizedparticle size to obtain consistency regardless of the surroundingatmosphere.

Dosing Aerosolized Drugs

Based on the above, it will be understood that the dosing or amount ofanalgesic drug actually released from the device can be changed based onthe most immediately prior monitoring event wherein the inspiratory flowof a patient's inhalation is measured.

Variations in doses are calculated by monitoring the effect ofrespiratory rate in response to known amounts of analgesic drug releasedfrom the device. If the response in decreasing the patient's respiratoryrate is greater than with previous readings, then the dosage isdecreased or the minimum dosing interval is increased. If the responsein decreasing respiratory rate is less than with previous readings, thenthe dosing amount is increased or the minimum dosing interval isdecreased. The increases and decreases are gradual and are preferablybased on averages (of 10 or more readings of respiratory rates after 10or more dosing events) and not a single dosing event and monitoringevent with respect to respiratory rates. The present invention canrecord dosing events and respiratory rates over time, calculate averagesand deduce preferred changes in administration of analgesic drug.

One of the important features and advantages of the present invention isthat the microprocessor can be programmed to take two different criteriainto consideration with respect to dosing times. Specifically, themicroprocessor can be programmed so as to include a minimum timeinterval between doses i.e. after a given delivery another dose cannotbe delivered until a given period of time has passed. Secondly, thetiming of the device can be programmed so that it is not possible toexceed the administration of a set maximum amount of drug within a giventime. For example, the device could be programmed to prevent dispersingmore than 200 micrograms of a narcotic within one hour. Moreimportantly, the device can be programmed to take both criteria intoconsideration. Thus, the device can be programmed to include a minimumtime interval between doses and a maximum amount of drug to be releasedwithin a given time period. For example, the microprocessor could beprogrammed to allow the release of a maximum of 200 micrograms of anarcotic during an hour which could only be released in amounts of 25micrograms with each release being separated by a minimum of fiveminutes.

The dosing program can be designed with some flexibility. For example,if the patient normally requires 25 mg per day of analgesic drug, themicroprocessor of the inhalation device can be programmed to preventfurther release of the valve after 35 mg have been administered within agiven day. Setting a slightly higher limit would allow for the patientto administer additional analgesic drug, if needed, due to a higherdegree of pain and/or account for misdelivery of analgesic drug such asdue to coughing or sneezing during an attempted delivery.

The ability to prevent overdosing is a characteristic of the device dueto the ability of the device to monitor the amount of analgesic drugreleased and calculate the approximate amount of analgesic drugdelivered to the patient based on monitoring given events such as therespiratory rate. The ability of the present device to preventoverdosing is not merely a monitoring system which prevents furthermanual actuation of a button. As indicated above, the device used inconnection with the present invention is not manually actuated, but isfired in response to an electrical signal received from a microprocessor(which received data from a monitoring device such as a device whichmonitors inspiratory flow) and allows the actuation of the device uponachieving an optimal point in a inspiratory cycle. When using thepresent invention, each release of the valve is a release which willadminister drug to the patient in that the valve is released in responseto patient inhalation. More specifically, the device does not allow forthe release of analgesic drug merely by the manual actuation of a buttonto fire a burst of analgesic drug into the air or a container.

The microprocessor will also include a timing device. The timing devicecan be electrically connected with visual display signals as well asaudio alarm signals. Using the timing device, the microprocessor can beprogrammed so as to allow for a visual or audio signal to be sent whenthe patient would be normally expected to administer analgesic drug. Inaddition to indicating the time of administration (preferably by audiosignal), the device can indicate the amount of analgesic drug whichshould be administered by providing a visual display. For example, theaudio alarm could sound alerting the patient that analgesic drug shouldbe administered. At the same time, the visual display could indicate "50μg" as the amount of analgesic drug to be administered. At this point, amonitoring event could take place. After completion of the monitoringevent, administration would proceed and the visual display wouldcontinually indicate the remaining amount of analgesic drug which shouldbe administered. After the predetermined dose of 50 μg had beenadministered, the visual display would indicate that the dosing eventhad ended. If the patient did not complete the dosing event byadministering the stated amount of analgesic drug, the patient would bereminded of such by the initiation of another audio signal, followed bya visual display instructing the patient to continue administration.

Additional information regarding dosing with analgesic drug viainjection can be found within Anesthesa, (most recent edition) edited byMiller, and published by Churchill and Livingston andHarrison's--Principles of Internal Medicine (most recent edition)published by McGraw Hill Book Company, New York, incorporated herein byreference to disclose conventional information regarding dosinganalgesic drug via injection.

Supplemental Treatment Methodology

Patients suffering from pain may be treated solely with analgesic drugas indicated above, i.e. by intrapulmonary delivery. However, it ispossible to treat such patients with a combination of analgesic drug(s)provided by other means of administration. More specifically, a patientcan be provided with a basal level of analgesic drug by a means such astransdermal administration and/or oral administration. This basal levelof drug will be sufficient to control the pain of the patient duringnormal circumstances. However, when the pain becomes more intense, thepatient can quickly obtain relief by the intrapulmonary administrationof an analgesic drug such as sufentanil using the device and methodologyof the present invention. The intrapulmonary delivery of analgesic drugprovides a pulsalite rate increase over the normal basal rate levelmaintained by the oral or transdermal administration. The use of theintrapulmonary administration of analgesic drug via the presentinvention is particularly desirable in that the effects of the drug arefelt almost immediately. Such an immediate effect cannot be obtainedusing oral and/or transdermal administration means.

Fentanyl is available for administration by a transdermal deliverysystem in the form of a skin patch [Duragesic™ (fentanyl transdermalsystem) package insert, Janssen Pharmaceutica, Piscataway, N.J. 08855,Jan.-Jun. 1991].

In addition to administering narcotics by transdermal administration itis possible to administer the drugs by other means such as by injectionand/or orally. In accordance with the present invention a preferredsupplemental means of administration is oral in that oral administrationcan be carried out on an out-patient basis. Thus, the method of theinvention may be carried out by administering a long acting orallyeffective narcotic drug. The oral drug is preferably given in amount soas to maintain a relatively low level of narcotic within the circulatorysystem which is sufficient to control pain during periods when the painis less severe. However, this low level of drug to blood ratio must beraised in order to control more severe pain and such can be accomplishedby the interpulmonary administration of narcotic using the presentinvention.

Based on the above, it will be understood by those skilled in the artthat a plurality of different treatments and means of administration canbe used to treat a single patient. For example, a patient can besimultaneously treated with analgesic drug by injection, analgesic drugvia intrapulmonary administration in accordance with the presentinvention, and drugs, which are orally administered. Should such proveto be ineffective for whatever reason, such as breathing difficulties(not related to the administration of the analgesic drug), such could besupplemented by administration via injection.

Treating Overdoses with Narcotic Antagonist

The methodologies of the present invention can be carried out using anytype of analgesic drug, although they are preferably carried out usingpotent narcotic such as fentanyl and morphine. The biochemical mechanismof action of such narcotics is known. Further, it is known that thenarcotic effect can be blocked by the administration of a narcoticantagonist such as naloxone. The devices and methodology disclosed anddescribed herein may be used to deliver narcotic antagonists such asnaloxone.

Controlled Access of Toxic Drugs

Although the primary purpose of the present invention is to provide adevice and methodology for controlling access to narcotic drugs thedevice and methodology can also be used to control access to certaintoxic drugs. This is particularly important when the drugs might bebrought into contact with children. For example, drugs such as insulincan be delivered using methodology such as that disclosed herein. Forexample, see U.S. patent application Ser. No. 08/011,281 filed Jan. 29,1993, entitled "Method of Administration of Insulin" incorporated hereinby reference. In that the administration of insulin to a patient not inneed of insulin could be toxic, the electronic locking devices of thepresent invention could be used to prevent delivery of the insulin orany toxic drug to unauthorized users.

Treatment of Drug Addicts

Attempts at treating drug addicts can involve the administration ofcertain drugs to the patient. However, since the drugs beingadministered are controlled substances the treatment programs oftenrequire that the patient being treated return to a drug treatment clinicon a daily basis. In part because it is difficult to convince suchpatients to continue treatment when they must return to a specificclinic on a daily basis, the treatment programs often fail. By using themethodology and devices of the present invention it is possible toprovide a drug addict being treated with a device which includes a largenumber of doses of drug for treatment. The, device could be programmedso that it could not be accessed by others and can be programmed so thatit will not release more than a preprogrammed amount of drug during apreprogrammed amount of time.

Delivery Device

There are two preferred types of devices which can be used with thepresent invention. In general, one type uses a low boiling pointpropellant and the other uses aqueous formulations. The devices whichuse low boiling point propellants are shown in FIGS. 1-4 and anembodiment of a device which uses aqueous formulations is shown in FIG.10. Regardless of which type is used the device is a hand-held, portabledevice which is comprised of (a) a means for separately measuring andanalyzing the inspiratory flow rate and inspiratory volume of a patientand (b) a means for automatically releasing a measured amount of anarcotic into the inspiratory flow path of a patient, e.g. an automaticvalve actuation means or mechanism for moving formulation through aporous membrane. In order to use the device, the device must be"loaded", i.e. connected to (c) a source of pain relieving drug which,in general, is a potent narcotic drug in water or in a low boiling pointpropellant. The entire device is light weight (less than 1 kg loaded)and portable.

A formulation of an analgesic drug in a low boiling point propellant istypically contained in a pressurized canister which is connectable tothe "unloaded" device, i.e., the device without the container.Particularly preferred narcotic formulations of this type are disclosedin U.S. patent application Ser. No. 08/242,223 filed Jun. 16, 1993 whichis incorporated herein by reference to disclose such formulations. Whenthe container of propellant and analgesic drug is connected to thedevice, the container will include a valve opening at one end whichopening is seated into a flow path within the device. The devicepreferably includes a mouth piece at the end of the flow path, and thepatient inhales from the mouth piece which causes an inspiratory flow tobe measured within the flow path. This inspiratory flow causes an airflow transducer to generate a signal. This signal is conveyed to amicroprocessor which is able to convert, continuously, the signal fromthe transducer in the inspiratory flow path to a flow rate in liters perminute. The microprocessor can further integrate this continuous airflow rate signal into a representation of cumulative inspiratory volume.At an appropriate point in the inspiratory cycle, the microprocessor cansend a signal to an actuation means. When the actuation means issignaled, it releases a valve allowing analgesic drug and propellant toescape into the inspiratory flow path of the device and ultimately intothe patient's lungs. After being released, the drug and propellant willpreferably pass through a nozzle prior to entering the inspiratory flowpath of the device and thereafter the lungs of the patient.

It is important to note that the firing threshold of the device is notbased on a single criterion such as the rate of air flow through thedevice or a specific time after the patient begins inhalation. Thefiring threshold is based on an analysis of the patient's inspiratoryflow profile. This means that the microprocessor controlling the devicetakes into consideration the instantaneous air flow rate as well as thecumulative inspiratory flow volume when it determines the optimal pointin the patient's inspiratory cycle which would be most preferable interms of reproducibly delivering the same amount of drug to the patientwith each release of drug. The high degree of dosing repeatabilityneeded to deliver narcotics may be obtained merely by measuring andreleasing at the same measure flow rate and volume for each release ofdrug. Further, the device preferably includes a means for recording acharacterization of the inspiratory flow profile for the patient whichis possible by including a microprocessor in combination with aread/write memory means and a flow measurement transducer. By using suchdevices, it is possible to change the firing threshold at any time inresponse to an analysis of the patient's inspiratory flow profile, andit is also possible to record drug dosing events over time.

FIG. 1 shows a cross-sectional view of a hand-held, portable, electronicbreath-actuated inhaler device which can be used in connection with thepresent invention. The device is shown with a holder 1 havingcylindrical side walls and a removable cap. The holder 1 is "loaded" inthat it includes the pressurized canister 3. The canister 3 includes anon-metering valve 5 which is held down in the open position when thecap 2 is screwed down, thus setting the valve 5 into a seat 6 which isin connection with a flow path 8.

A formulation 4 comprised of a narcotic such as sufentanil or fentanyland a suitable propellant, such as a low boiling point propellant, iscontained within the pressurized canister 3. Propellant and narcoticdrug are released from the canister 3 via the electrically controlledsolenoid 7. In that the valve 5 of the canister is continuously open,another valve, contained within solenoid 7, facilitates the release ofthe drug. When the solenoid 7 allows release of propellant and drug, thepropellant and drug flows through the flow path 8 and then through thesolenoid actuated valve 9 into the flow path 10, out through the nozzle13 and then into the inspiratory flow path 11 surrounded by walls 12.

It is important to note that a variety of devices can be used in orderto carry out the pain management delivery methodology of the presentinvention. However, the device must be capable of allowing the releaseof a metered amount of analgesic drug based on pre-programmed criteriarelating to flow rate and volume. These measurements may be mademechanically but are preferable electronic and are readable by themicroprocessor 22. The pre-programmed information is contained within anonvolatile memory which can be modified via an external device. Inanother embodiment, this pre-programmed information is contained withina "read only" memory which can be unplugged from the device and replacedwith another memory unit containing different programming information.In yet another embodiment, microprocessor 22, containing read onlymemory which in turn contains the pre-programmed information, is pluggedinto the device. For each of these three embodiments, changing theprogramming of the memory device readable by microprocessor 22 willradically change the behavior of the device by causing microprocessor 22to be programmed in a different manner. As regards the presentinvention, the non-volatile memory contains information relevant only tothe administration of a specific analgesic drug such as fentanyl.Microprocessor 22 sends signals to solenoid 7 which determines theamount of drug delivered into the inspiratory flow path. Further,microprocessor 22 keeps a record of all drug dosing times and amountsusing a read/write non-volatile memory which is in turn readable by anexternal device. The formulation 4 contained within canister 3 isreleased into the atmosphere ultimately via nozzle 13 which opens intoinspiratory flow path 11. It is at this point that the low boiling pointpropellant within formulation 4 flashes, i.e. rapidly evaporates, thusproviding particles of analgesic drug in an aerosol which is introducedinto the mouth and ultimately into the lungs of the patient. In order toallow for ease of use, it is possible to form inspiratory flow path 11into a mouth piece which can be specifically designed to fit the mouthof a particular patient using the device.

The solenoid 7, and associated valve 9, flow paths 8 and 10, as well asnozzle 13 make up the aerosol delivery system 14 shown by the dottedlines within FIG. 1. The system 14 is in connection with the flow sensor15 which is capable of measuring a flow rate of about 0 to about 300liters per minute. The flow sensor 15 includes screens 16, 17 and 18which are positioned approximately 1/4" apart from each other. Tubes 19and 20 open to the area between the screens 16, 17 and 18 with the tubes19 and 20 being connected to a conventional differential pressuretransducer 21. When the user draws air through inspiratory flow path 11,air is passed through the screens 16, 17 and 18 and the air flow can bemeasured by the differential air pressure transducer 21. The flow sensor15 is in connection with the aerosol delivery system 14, and when athreshold value of air flow is reached, the aerosol delivery system 14allows the release of formulation 4 so that a controlled amount ofanalgesic drug is delivered to the patient. Solenoid 7 is connected to amicroprocessor 22 via an electrical connection. The details of themicroprocessor and the details of other drug delivery devices whichmight be used in connection with the present invention are described anddisclosed within U.S. patent application Ser. No. 07/664,758, filed onMar. 5, 1991 entitled "Delivery of Aerosol Medications for Inspiration"which application is incorporated in its entirety herein by reference,and it is specifically incorporated in order to describe and disclosedevices as shown within FIG. 1 and the microprocessor and programtechnology used therewith.

A cross-sectional view of yet another (and more preferred) embodiment ofthe hand-held, electronic, breath-actuated inhaler device of theinvention is shown in FIG. 2. The device of FIG. 2 shows all of thecomponents present within the single hand-held, portable device, i.e.the power source not shown in FIG. 1 is shown in the device in FIG. 2.Like the device shown within FIG. 1, the device of FIG. 2 includes acanister 3 which includes a canister valve 5. However, unlike the deviceof FIG. 1, the device of FIG. 2 does not have the valve continuouslyopen but allows a valve 5 connected to the canister 3 to be opened bythe mechanical force generated by a valve actuation mechanism 26 whichis a motor driven, mechanical mechanism powered by a power source suchas batteries 23 and 23'. However, like the device shown within FIG. 1,the patient inhales through inspiratory flow path 11 which can form amouth piece in order to obtain a metering event using the differentialpressure transducer 21. Further, when the inspiratory flow meets athreshold of a pre-programmed criteria, the microprocessor 24 sends asignal to an actuator release mechanism 25 which actuates the actuationmechanism 26 forcing canister 3 downward so that canister valve 5releases formulation into the inspiratory flow path 11. Further detailsregarding the device of FIG. 2 are described within co-pending U.S.patent application entitled "An Automatic Aerosol Medication DeliverySystem and Methods", filed on Jan. 29, 1993 as Ser. No. 08/002,507,which application is incorporated herein by reference in its entiretyand specifically incorporated in order to describe and disclose devicesas shown within FIG. 2 and the microprocessor and program technologyused therewith.

Microprocessor 24 of FIG. 2 includes an external non-volatile read/writememory subsystem, peripheral devices to support this memory system,reset circuit, a clock oscillator, a real time clock module, a dataacquisition subsystem and an LCD annunciator subsystem. The discretecomponents are conventional parts which have input and output pinsconfigured in a conventional manner with the connections being made inaccordance with instructions provided by the device manufacturers. Themicroprocessor used in connection with the device of the invention isdesigned and programmed specifically so as to provide controlled andrepeatable amounts of analgesic drug to a patient upon actuation.Adjustments can be made in the program so that when the patient'sinspiratory flow profile is changed such is taken into consideration.This can be done by allowing the patient to inhale through the device asa test in order to measure air flow with preferred drug delivery pointsdetermined based on the results of several inhalations by eachparticular patient. This process can be readily repeated when theinspiratory flow profile is changed for whatever reason, e.g. abdominalincisional pain resulting in low tidal volumes. Determination of optimaldrug delivery points in the inspiratory flow can be done at each dosingevent, daily, weekly, or with the replacement of a new canister in thedevice.

The microprocessor of the present invention, along with its associatedperipheral devices, can be programmed so as to prevent the release ofdrug from the canister from occurring more than a given number of timeswithin a given period of time. This feature makes it possible to preventoverdosing the patient with a potent narcotic. The overdose preventionfeature can be particularly designed with each individual patient inmind or designed with particular groups of patients in mind. Forexample, the microprocessor can be programmed so as to prevent therelease of more than approximately 200 μg of fentanyl per day when thepatient is normally dosed with approximately 100 μg of fentanyl per day.The systems can also be designed so that only a given amount of aparticular analgesic drug is provided at a given dosing event. Forexample, the system can be designed so that only approximately 100 μg offentanyl is given in a given 15-minute period over which the patientwill make approximately 10 inhalations with 10 μg of fentanyl beingdelivered with each inhalation. By providing this feature, greaterassurances are obtained with respect to delivering the analgesic druggradually over time and thereby providing pain management withoutoverdosing the patient.

Access to a drug in the device is controlled by electronicallyinterconnecting the microprocessor of the drug delivery device justdescribed (FIG. 2) to an electronic lock means which can be accessedonly with an electronic key device. The microprocessor of the drugdelivery device is programmed to not release drug if it does not receivea signal transmitted to it by an electronic lock means coupled to amatching coded electronic key means worn by the intended user. Such asystem prevents abuse by unauthorized users.

An electronic lock and key mechanism such as the TSN described in FIG.11 has an electrical interface comprised of a metallic cylindricalhousing which holds the TSN and has two contacts. The front surface ofthe housing acts as the data I/O line into the device, while the backand side surfaces act as the signal ground. The TSN I/O line isbidirectional and the line is preferably connected to an open-drain ortri-state driver. The TSN I/O line is preferably pulled up with a 5Kresistor. The idle state for this line is high; during idle periods, theTSN draws power from the host via this signal.

The microprocessor of the lock means is reset prior to reading data fromthe TSN (see FIG. 11). The microprocessor initiates the reset by drivingthe I/O line low preferably for at least 480 μs, then releasing the line(i.e., allowing the line to return to its default high level). The TSNwill acknowledge the reset by waiting approximately at least 15 μs andnot more than approximately 60 μs, Then driving this line low for atleast approximately 60 μs and not more that approximately 240 μs, thenreleasing the line. The microprocessor of the lock means is preferablyprogrammed to allow at least approximately 480 μs for the TSN tocomplete this acknowledgement.

After the TSN has been reset, the command byte, which equals φFhexadecimal, is written into the TSN before its ROM data may be read.This command is written into the TSN one bit at a time, leastsignificant bit first.

Preferably, a write cycle is initiated by the microprocessor of the lockmeans by bringing the I/O line low for approximately 1-15 μs (see FIG.10). If the microprocessor of the lock means is writing a "0", itcontinues to hold this line low for a total low time of approximately60-120 μs. The TSN samples this line approximately 15-60 μs after thestart of the low-going pulse. After the "0" has been written, the hostmust release this line for at least approximately 1 μs to allow the TSNto draw power from the line.

If a "1" is being written to the TSN, the microprocessor of the lockmeans releases the I/O line after generating its approximately 1-15 μspulse; the pull-up resistor then pulls this signal high. As before, theTSN samples this line approximately 15-60 μs after the start of thelow-going pulse, so this write period should be a minimum ofapproximately 60 μs in duration. After the "1" has been written, themicroprocessor of the lock means preferably waits at least approximately1 μs before beginning the next bit transaction.

After the command byte, which equals φF hexadecimal, has been sent tothe TSN, its ROM data may be read (see FIG. 11). The TSN will firsttransmit its family code (for example, φ1 hexadecimal), followed by aunique 48 bit serial number, followed by a single CRC byte encompassingthe family and serial number data. All data are preferably transmittedby the least significant bit first.

A read cycle is initiated by the microprocessor of the lock means bydriving the I/O line low for approximately 1-15 μs, then releasing it.If the TSN data bit is a "0", the TSN will drive this line low forapproximately 15-60 μs after the start of the low-going pulse, afterwhich it will release the line. If the TSN data bit is a "1", the TSNwill leave the I/O line unaffected.

Preferably, the lock means microprocessor's low going pulse is as closeto 1 μs as possible to maximize its valid read window. The lock meansmicroprocessor preferably samples the signal no more than 15 μs afterinitiating the read cycle. The entire read period should be at least 60μs long, after which the lock means microprocessor preferably waits atleast approximately 1 μs before beginning the next bit transaction.

The microprocessor of the invention can be connected to external devicespermitting external information to be transferred into themicroprocessor of the invention and stored within the non-volatileread/write memory available to the microprocessor. The microprocessor ofthe invention can then change its drug delivery behavior based on thisinformation transferred from external devices. All of the features ofthe invention are provided in a portable, programmable, battery-powered,hand-held device for patient use which has a size which comparesfavorably with existing metered dose inhaler devices.

The microprocessor of the present invention is programmed so as to allowfor monitoring and recording data from the inspiratory flow monitorwithout delivering drug. This is done in order to characterize thepatient's inspiratory flow profile in a given number of monitoringevents, which monitoring events preferably occur prior to dosing events.After carrying out a monitoring event, the preferred point within theinspiratory cycle for drug delivery can be calculated. This calculatedpoint is a function of measured inspiratory flow rate as well ascalculated cumulative inspiratory flow volume. This information isstored and used to allow activation of the valve when the inhalationcycle is repeated during the dosing event. The devices of FIGS. 1 and 2have been put forth in connection with devices which use a low boilingpoint propellant and preferably use that propellant in combination witha suspension formulation which includes the dry powdered analgesic drugwithin the low-boiling-point propellant. Those skilled in the art willreadily recognize that such devices can be used for administering asolution of analgesic drug within the low-boiling-point propellant.However, those skilled in the art will also readily recognize thatdifferent mechanisms will be necessary in order to deliver differentformulations, such as a dry powder without any propellant. A devicecould be readily designed so as to provide for the mechanical movementof a predetermined amount of dry powder to a given area. The dry powderwould be concealed by a gate, which gate would be opened in the samemanner described above, i.e., it would be opened when a predeterminedflow rate level and cumulative volume have been achieved based on anearlier monitoring event. Patient inhalation would then cause the drypowder to form a dry dust cloud and be inhaled. Dry powder can also beaerosolized by compressed gas, and a solution can be aerosolized by acompressed gas released in a similar manner and then inhaled.

Aqueous System Device

The device of FIGS. 1 and 2 can be used to deliver a formulation ofnarcotic drug and low boiling point propellant. The system shown in FIG.10 is used to deliver a formulation of analgesic drug (e.g. narcotics)in a carrier of water and/or ethanol. An embodiment of such a devicewill now be described in detail.

The device 50 shown in FIG. 10 is loaded with a disposable package 51.To use the device 50 a patient (not shown) inhales air from themouthpiece 52. The air drawn in through the opening 53 and flows throughthe flow path 54. The package 51 is comprised of a plurality ofcontainers 55. Each container 55 includes a drug formulation 56 and isin fluid connection via a channel 57 with the cavity 58. The cavity 58is covered by the porous membrane 59. A vibration device 60 may bepositioned directly below the cavity 58.

The device 50 is a hand-held, portable device which is comprised of (a)a device for holding a disposable package with at least one butpreferably a number of drug containers, (b) a mechanical mechanism (e.g.piston or vibrator for moving the contents of a container (on thepackage) through a porous membrane (c) a device for separately measuringthe inspiratory flow rate and inspiratory volume of a patient, and (d) aswitch for automatically releasing or firing the mechanical means afterthe inspiratory flow rate and/or volume reaches a predetermined point.If the device is electronic it also includes (e) a source of power.

The device for holding the disposable package may be nothing more than anarrow opening created between two outwardly extending bars or mayinclude additional components such as one or more wheels, sprockets orrollers notably mounted on the end(s) of such bars. The rollers may bespring mounted so as to provide constant pressure against the surface(s)of the package. The device may also include a transport mechanism whichmay include providing drive power to roller(s) so that when they arerotated, they move the package from one container to the next. A powersource driving the roller(s) can be programmed to rotate the rollersonly enough to move the package from one container to the next. In orderto use the device, the device must be "loaded," i.e. connected to apackage which includes drug dosage units having liquid, flowableformulations of pharmaceutically active drug therein. The entire deviceis self-contained, light weight (less than 1 kg preferably less than 0.5kg loaded) and portable.

FIG. 10 shows a cross-sectional view of a hand held, self-contained,portable, breath-actuated inhaler device 50 which can be used in themethod of the present invention. The device 50 is shown with a holder 60having cylindrical side walls and a hand grip 61. The holder 2 is"loaded" in that it includes a package 51. The package 51 includes aplurality of containers 56 connected by a connecting member 65.

The embodiment shown in FIG. 10 is a simple version of a device 50 whichmay be manually actuated and loaded. More specifically, the spring 62may be compressed by the user until it is forced down below theactuation mechanism 63. When the user pushes the actuation mechanism 63the spring 62 is released and the mechanical means in the form of aplate 24 is forced upward against a container 56. When the container 56is compressed its contents are forced out through the channel 57 andmembrane 59 and aerosolized. Another container 56 shown to the left isunused. A top cover sheet 64 has been peeled away from the top of themembrane 59 by a peeling means 25. The embodiment of FIG. 10 couldprovide the same results as a conventional metered dose inhaler.However, the device of FIG. 10 would not require the use of low boilingpoint propellants such as low boiling point fluorocarbons. Numerousadditional features and advantages of the present invention can beobtained by utilizing the monitoring and electronic components describedbelow.

The device must be capable of aerosolizing drug formulation in acontainer and preferably does such based on pre-programmed criteriawhich are readable by the microprocessor 26. The details of themicroprocessor 26 and the details of other drug delivery devices whichinclude a microprocessor and pressure transducer of the type used inconnection with the present invention are described and disclosed withinU.S. patent application Ser. No. 07/664,758 filed on Mar. 5, 1991entitled "Delivery of Aerosol Medications for Inspiration" whichapplication is incorporated in its entirety herein by reference, and isspecifically incorporated in order to describe and disclose themicroprocessor and program technology used therewith. The use of such amicroprocessor with a drug delivery device is disclosed in our earlierfiled U.S. patent application Ser. No. 08/065,660 filed May 21, 1993incorporated herein by reference. The pre-programmed information iscontained within a nonvolatile memory which can be modified via anexternal device. In another embodiment, this pre-programmed informationis contained within a "read only" memory which can be unplugged from thedevice and replaced with another memory unit containing differentprogramming information. In yet another embodiment, microprocessor 26,containing read only memory which in turn contains the pre-programmedinformation, is plugged into the device. For each of these threeembodiments, changing the programming of the memory device readable bymicroprocessor 26 will radically change the behavior of the device bycausing microprocessor 26 to be programmed in a different manner. Thisis done to accommodate different analgesic drugs.

Microprocessor 26 sends signals via electrical connection 27 toelectrical actuation device 28 which actuates the means 63 which firesthe mechanical plate 24 forcing drug formulation in a container 56 to beaerosolized so that an amount of aerosolized drug is delivered into theinspiratory flow path 54. The device 28 can be a solenoid, motor, or anydevice for converting electrical to mechanical energy. Further,microprocessor 26 keeps a record of all drug dosing times and amountsusing a read/write non-volatile memory which is in turn readable by anexternal device. Alternatively, the device records the information ontoan electronic or magnetic strip on the package 51. The recordedinformation can be read later by the care-giver to determine theeffectiveness of the treatment. In order to allow for ease of use, it ispossible to surround the inspiratory flow path 54 with a mouth piece 52.

The electrical actuation means 28 is in electrical connection with theflow sensor 31 which is capable of measuring a flow rate of about 0 toabout 800 liters per minute. It should be noted that inhalation flowrates are less than exhalation rates, e.g. max for inhalation 200 lpmand 800 lpm for exhalation. The flow sensor 31 includes screens 32, 33and 34 which are positioned approximately 1/4" apart from each other.

Tubes 35 and 36 open to the area between the screens 32, 33 and 34 withthe tubes 35 and 36 being connected to a conventional differentialpressure transducer 37. Another transducer designed to measure outflowthrough the opening 38 is also preferably included or the flow sensor 31is designed so that the same components can measure inflow and outflow.When the user draws air through inspiratory flow path 54, air is passedthrough the screens 32, 33 and 34 and the air flow can be measured bythe differential air pressure transducer 37. Alternatively, other meansto measure pressure differential related to air flow, such as aconventional measuring device in the air way, may be used. The flowsensor 31 is in connection with the electrical actuation means 28 (viathe connector 39 to the processor 26), and when a threshold value of airflow is reached (as determined by the processor 26), the electricalactuation means 28 fires the release of a mechanical means 63 releasingthe plate 24 which forces the release of formulation from a container 56so that a controlled amount of drug is delivered to the patient. Themicroprocessor 26 is also connected via connector 40 to an optionallypresent vibrating device 60 which may be activated.

Vibration Device

The ultrasonic vibrations are preferably at right angles to the plane ofthe membrane 14 and can be obtained by the use of a piezoelectricceramic crystal or other suitable vibration device 60. The vibratingdevice 60 in the form of a piezoelectric crystal may be connected to theporous membrane 59 by means of an attenuator horn or acoustic conductionmechanism, which when correctly matched with the piezoelectric crystalfrequency, efficiently transmits ultrasonic oscillations of thepiezoelectric crystal to the resonance cavity and the porouspolycarbonate membrane and if sized correctly permits the ultrasonicenergy to be focused in a polycarbonate membrane 59 allowing for maximumuse of the energy towards aerosolizing the liquid formulation 56. Thesize and shape of the attenuator horn is not of particular importance.It is preferred to maintain a relatively small size in that the deviceis hand held. The components are chosen based on the particular materialused as the porous material, the particular formulation used and withconsideration of the velocity of ultrasonic waves through the membraneto achieve a harmonic relationship at the frequency being used.

A high frequency signal generator drives the piezoelectric crystal. Thisgenerator is capable of producing a signal having a frequency of fromabout 800 kilohertz (Khz) to about 4,000 kilohertz. The power outputrequired depends upon the amount of liquid being nebulized per unit oftime and the area and porosity of the polycarbonate membrane used forproducing the drug dosage unit and/or the efficiency of the connection.

Vibration is applied while the formulation 56 is being forced from thepores of the polycarbonate membrane 59. The formulation can beaerosolized with only vibration i.e., without applying pressure.Alternatively, when vibration is applied in certain conditions thepressure required for forcing the liquid out can be varied depending onthe liquid, the size of the pores and the shape of the pores but isgenerally in the range of about one to 200 psi, preferably 50 to 125 psiand may be achieved by using a piston, roller, bellows, a blast offorced compressed gas, or other suitable device. The vibration frequencyused and the pressure applied can be varied depending on the viscosityof the liquid being forced out and the diameter and length of theopenings or pores. In general, the present invention does not createeffective aerosols if the viscosity of the liquid is greater than about50 centipoises.

When small aerosolized particles are forced into the air, the particlesencounter substantial frictional resistance. This may cause particles toslow down more quickly than desired and may result in particlescolliding into each other and combining, which is undesirable withrespect to maintaining the preferred particle size distribution withinthe aerosol. In order to aid in avoiding the particle collision problem,it is possible to include a means by which air or any other gas isforced through openings as the aerosol is forced out of the porousmembrane. Accordingly, an air flow is created toward the patient andaway from the nozzle opening which carries the formed particles alongand aids in preventing their collision with each other. The amount ofgas forced from the openings will vary depending upon the amount ofaerosol being formed. However, the amount of gas is generally five totwo hundred times the volume of the liquid formulation within thecontainer. Further, the flow velocity of the gas is generally aboutequal to the flow velocity of the aerosolized particles being forcedfrom the nozzle. The shape of the container opening, the shape of themembrane covering that opening, as well as the positioning and anglingof the gas flow and particle flow can be designed to aid in preventingparticle collision. When the two flow paths are substantially parallel,it is desirable to shape the opening and matching membrane so as tominimize the distance between any edge of the opening and the center ofthe opening. Accordingly, it is not desirable to form a circular openingwhich would maximize the distance between the outer edges of the circleand the center of the circle, whereas it is desirable to form anelongated narrow rectangle. Using such a configuration makes it possibleto better utilize the air flow relative to all of the particles beingforced form the container. When a circular opening is used, particleswhich are towards the center of the circle may not be carried along bythe air being forced from the openings and will collide with each other.The elongate rectangle could be formed in a circle, thereby providing anannular opening and air could be forced outward from the outer and inneredges of the circle formed. Further details regarding such are describedin U.S. patent application Ser. No. 08/247,012 filed May 20, 1994 whichis incorporated herein by reference to disclose and describe such.

Security Features

In that narcotic drugs are subject to drug abuse it is desirable todesign devices and methodology so as to hinder abuse to the extentpossible. The methodology and devices of the present invention do so inan number of specific ways.

The device shown within FIG. 2 is designed to be reusable. Morespecifically, the drug delivery device can be "loaded" with a cassetteof the type shown within either of FIGS. 3 and 4. The cassette iscomprised of an outer cover 30, a canister 3 and top nozzle piece 31.The components are shown in a disassembled state in FIG. 3. A differentembodiment of such components are shown in an assembled state withinFIG. 4.

In essence, the cassette shown in FIG. 3 is somewhat less secure thanthe cassette shown within FIG. 4. As indicated, the top portion of thecover 30 is open within FIG. 3. This allows one to force the canister 3downward and open the valve 5 to allow release of drug. However, in theembodiment shown in FIG. 4, there is no general opening but only twosmall openings 34 and 34'. Using the embodiment shown in FIG. 3, thecassette is loaded within the device shown in FIG. 2 and a motor drivenpiston forces the bottom of the canister 3 downward actuating the valve5 to an open position. In accordance with the embodiment shown withinFIG. 4, a two-pronged fork device is positioned over the end portion ofthe cover 30'. Each prong of the fork protrudes through an opening 34and 34' allowing the canister 3 to be forced downward so that the valve5 can be opened. It should be pointed out that when the cover 30 isattached to the top nozzle piece 31, they can be sealed together using afast-acting glue or any appropriate means making it impossible toseparate the components.

In that the narcotic drug is contained within the canister 3 with a lowboiling point propellant it is extremely difficult to open the canisterwithout losing all of the contents. Accordingly, the contents of thecanister can generally be obtained only by including the canister withincomponents 30 and 31 and attaching such to the device shown within FIG.2.

The following description is provided with respect to FIG. 3 and thecomponent shown therein, but is equally applicable with respect to FIG.4 and the component shown therein. The cover 30 can have protuberancessuch as the protuberance 32 and openings such as the opening 33 thereon.These openings and protuberances can serve as a type of lock and keymechanism which is interactable with receiving protuberances andopenings in the device shown in FIG. 2. Accordingly, unless the cover 30includes the correct openings and protuberances in the correct positionthe cover will not fit into the device shown in FIG. 2 and cannot beoperated. The body of the device as shown within FIG. 2 is designed soas to be capable of receiving the openings and protuberances on thecover 30. Although devices such as those shown within FIG. 2 might beutilized to dispense a variety of different types of drugs the physicalconfiguration of the device is specific with respect to certain drugsand is particularly specific with respect to narcotic drugs. Thus, thecover 30 and receiving body portion on the device of FIG. 2 are designedso that they can be integrated but are also designed so that they willnot integrate with other devices not specific for the delivery ofnarcotic drugs. Thus, as a first layer of security the device andmethodology of the present invention provides for a physical lock andkey interaction.

As a second line of defense against misuse of drugs, it is possible todesign the components 31 and 32 and/or the device shown in FIG. 2 so asto receive a signal from a remote transmitter which is worn by thepatient for which the drug was prescribed by the prescribing physician.By designing the device in this manner no drug can be released from thedevice unless the device is in close proximity to the intended user ofthe device.

A more preferred embodiment of a controlled access device is describedherein as an electronic key device such as a Touch Serial Number (DallasSemiconductor) device. Using this electronic key access to a drug in adelivery device such as an aerosol device disclosed herein is restrictedto those patients possessing a code-matching TSN that is provided by thepatients physician or other health professional upon prescription of thedrug and the delivery device. The TSN is preferably worn by the intendeduser (the patient) on a bracelet or badge for convenient use with thedelivery device. Further, the TSN is unavailable to unintended users toprevent unintended users from accessing the drug (such a legallycontrolled narcotic or other toxic drug).

It will, of course, be apparent to those skilled in the art that acombination of all or any of the above security features can be used.Further, the transmitting and receiving signals can be by any means ofsignalling and need not be limited to radio signals and thus couldinclude infrared and other types of signals. Further, other interlockingmechanisms with more complex physical shapes could be readily devised inorder to enhance the security of the device.

As indicated above, the valve actuation means can be electronicallyprevented from allowing the release of valves. As further indicatedabove, this is generally done for purposes of security. However, suchcan also be implemented in order to prevent accidental overdosing by agiven patient. For example, the monitoring components of the inventioncan be designed so as to read the patients respiratory rate. If therespiratory rate is below a given value assigned to the particularpatient then the electronics can prevent the release of any drug fromthe device. It is well known that respiratory rates slow when largeamounts of narcotics are administered to a patient. Accordingly, if thepatients respiratory rate has been slowed to a dangerously low rate itis important to prevent further administration of drug to the patient.

Lock and Key

The present invention includes methodology for dispensing aerosolizeddrugs and a device which dispenses aerosolized drugs when activated. Thedrug dispensing device may be deactivated by a "lock" which lock may beof a variety of different types and may be "unlocked" by a variety ofdifferent types of keys. For example, the "lock" on the device may be aninternal microprocessor of the device which must be activated by thereceipt of a unique electronic code which code is sent by a key.Alternatively, the lock may be a bar code reader which after reading anappropriate bar code (the key) sends a signal which activates amicroprocessor control device which essentially turns the drugdispensing device on so that it may be used to dispense aerosolizeddrug. In another embodiment, the lock is a device which receivesinfrared signals and is activated by the receipt of a unique infraredsignal (the key) and after being activated sends a signal to themicroprocessor so that the device is turned on and can be used for thedispensing of a predetermined amount of drug. After a predeterminedamount of drug has been dispensed, the device will again deactivate. Thedevice may be programmed so that it cannot be reactivated for a givenperiod of time even if it does receive the required information from anappropriate key. Those skilled in the art will contemplate a variety ofdifferent types of "lock" and "key" combinations which could be used inorder to prevent access to and/or activation of a drug dispensing devicewhich creates aerosolized drug formulation for inhalation by a patient.

The instant invention is shown and described herein in which isconsidered to be the most practical and preferred embodiments. It isrecognized, however, that the departures may be made therefrom which arewithin the scope of the invention and that obvious modifications willoccur to one skilled in the art upon reading this disclosure.

We claim:
 1. A hand-held, portable, self-contained device for theintrapulmonary delivery of aerosolized drug, comprising:a disposabledrug formulation container, the container having therein a formulationwhich includes a pharmaceutically active drug; a component for holdingthe disposable container; a means for aerosolizing the drug intoparticles for delivery to a patient; a prevention device which preventsaccess to the drug when activated and allows access to the drug whendeactivated wherein activation and deactivation are obtained uponreceipt of a unique code from a source external to the body of thedevice; and a key, external to the body of the device, which providesthe unique code to the prevention device; wherein the drug is in aliquid formulation which is present in the disposable container whichincludes a disposable porous membrane which creates inhalableaerosolized particles when the formulation is moved through the pores.2. The device of claim 1 wherein the pores have a diameter in the rangeof from about 0.25 to about 2.5 microns.
 3. The device of claim 1,further comprising:a monitor which measures inspiratory flow rate andinspiratory volume of a patient.
 4. The device of claim 3, furthercomprising:a component which automatically activates the means foraerosolizing the drug upon receipt of a signal generated after theinspiratory flow rate and inspiratory volume reach a given level.
 5. Thedevice as claimed in claim 4, wherein the means for aerosolizing thedrug is automatically actuated upon receipt of a signal when theinspiratory volume is in the range of about 0.1 to about 2.0 liters/sec.and the inspiratory volume is in the range of about 0.15 to about 0.80liters.
 6. The device of claim 1, wherein the prevention device isactivated by a signal from a bar code reader and further wherein the keyis a readable bar code.
 7. The device as claimed in claim 1, wherein theprevention device is activated by a signal from an infrared receivingdevice and further wherein the key is a device which generates aninfrared signal.
 8. The device of claim 1, wherein the prevention deviceis activated by a signal from a device which reads electronicallyinformation and further wherein the key is a key comprised ofelectronically encoded information.
 9. The device of claim 1, whereinthe prevention device is activated by a device for receiving atransmitted signal and further wherein the key is a device for sending atransmitted signal.
 10. The device as claimed in claim 9, wherein thedevice for receiving the signal is a device for receiving an radiofrequency signal and the key is a device which sends an encoded radiofrequency.
 11. The device as claimed in claim 1, wherein the preventiondevice remains activated until it receives a signal from a respiratoryrate monitor means indicating that a measured respiratory rate is abovea predetermined minimum respiratory rate.